Infectious agents may contribute to the causation of up to 30% of cancers in humans, including viruses associated with liver, cervical, penile, and nasopharyngeal cancer, parasites with liver and bladder cancer, and the bacterium Helicobacter pylori with gastric cancer. The liver pathogen Helicobacter hepaticus was discovered six years ago in strain A/J mice being used in a bioassay in this Laboratory. Slowly progressing hepatitis in these mice culminated in a high incidence of benign and malignant liver tumors, providing an important animal model for study of mechanisms of infection-related cancer.Based on previous observations, we have hypothesized that a tumor promotion-like phenomenon contributes to the causation of liver tumors by H. hepaticus, perhaps involving chronic upregulation of oncogenes. In support of this, we found that both epidermal growth factor and transforming growth factor alpha are increased from an early stage of infection, with further increase in tumors. Similarly, cyclin D1, cyclin-dependent kinase 4 and c-myc increased early and progressively. An increase in cyclin D1-cyclin-dependent kinase 4 complex and in its functionality in phosphorylating the retinoblastoma protein were also shown. Data from recent and ongoing work are also confirmatory and had provided some additional useful insights. We have found that the adaptor protein Grb2, which bridges cell surface tyrosine kinase receptors with downstream signal transmitters such as ras p21, is upregulated in inflammatory lesions and in all preneoplastic and neoplastic lesions associated with H. hepaticus infection. This would insure effectiveness of the upregulated growth factor signals. This is the first demonstration of possible involvement of Grb2 in liver tumorigenesis. In a related study, we have found a significant increase in protein kinase C alpha and delta and ras p21, late in the tumorigenic process, whereas activated extracellularly regulated kinases 1 and 2 did not change at any time. Cooperation between oncogenic growth factors and their receptors, cell cycle proteins, and transcription factors is suggested as a mechanism for the early changes setting the stage for development of hepatocellular neoplasms, with several isoforms of PKC playing a role during tumor progression. A stress-related signal pathway, rather than the Erk/MAPK route, may be in play. - Cell cycle control, Grb2, protein kinase C, ras p, , Helicobacter, Infection, Liver, tumor promotion, - Neither Human Subjects nor Human Tissues